CC-486 and Venetoclax for Acute Myeloid Leukemia
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 35
- 试验地点
- 2
- 主要终点
- Determine the maximum tolerated dose of CC-486 in combination with venetoclax
研究概览
简要总结
This is an open label, dose escalation Phase I single institution pilot study for relapsed and refractory AML patients using CC-486 (oral azacitidine) with venetoclax. At the completion of dose escalation and after establishment of the MTD or recommended dose of CC-486 with venetoclax, an expansion phase will commence, using venetoclax with the MTD of CC-486 in relapsed/refractory patients.
详细描述
Subjects confirmed eligible will be admitted to the hospital for cycle 1, day 1. Venetoclax will be administered days 1-3, with the following schema:
100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter.
Subjects taking concomitant CYP3A4 inhibitors will be given the appropriate reduced doses of venetoclax.
Subjects will be monitored inpatient for tumor lysis syndrome (TLS) for at least 24 hours after administration of the venetoclax target dose. Venetoclax will continue at 400 mg daily until day 28, the completion of cycle 1.
During dose escalation, subjects will be accrued into two cohorts using two different doses of CC-486 (cohort 1=200 mg, cohort 2=300 mg, both to be administered orally on days 1-14 of a 28-day cycle).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 100 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Subject must have confirmation of non-APL AML by WHO criteria46 and have undergone at least one line of therapy (dose escalation and dose expansion R/R cohorts), or have had no prior lines of therapy (newly diagnosed cohort) Prior treatment with hydroxyurea or ATRA is allowed in the newly diagnosed cohort.
- •For the newly diagnosed cohort, subjects must be unlikely to tolerate standard intensive chemotherapy due to age, performance status, or comorbidities based on at least one of the following criteria:
- •a. age ≥75 years old OR b. age < 75 years old with at least one of the following: i. ECOG performance status of 3 ii. Cardiac history of CHF or documented EF ≤50% iii. pulmonary disease with DLCO ≤65% or FEV1 ≤65% iv. creatinine clearance ≥30 mL/min to < 45 mL/min based on the CKD-EPI Creatinine Equation (2021). https://www.kidney.org/content/ckd-epi-creatinine-equation-2021 v. any other comorbidity that the investigator judges to be incompatible with intensive chemotherapy
- •Patients must have ECOG of 0 to 3 (if < 75 years old) or 0 to 2 (if ≥75 years old)
- •Transplant eligible patients can participate in the study and they are allowed to proceed with stem cell transplantation at any time during the study.
- •Subject must have a projected life expectancy of at least 12 weeks.
- •Subject must have adequate renal function as demonstrated by a calculated creatinine clearance ≥ 30 mL/min; determined via urine collection for 24-hour creatinine clearance or by the Cockcroft Gault formula.
- •Subject must have adequate liver function as demonstrated by:
- •aspartate aminotransferase (AST) ≤ 3.0 × ULN*
- •alanine aminotransferase (ALT) ≤ 3.0 × ULN*
- •bilirubin ≤ 1.5 × ULN, unless due to Gilbert's syndrome* * Unless considered due to leukemic organ involvement
- •Non-sterile male subjects must use contraceptive methods with partner(s) at least prior to beginning study drug administration and continuing up to 90 days after the last dose of study drug. Male subjects must agree to refrain from sperm donation from initial study drug administration until 90 days after the last dose of study drug. No contraception is required if male subjects are surgically sterile (vasectomy with medical assessment confirming surgical success) or if the male subject has a female partner who is postmenopausal or permanently sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
- •Female subjects must be either:
- •Postmenopausal; defined as Age > 60 years with no menses for 12 or more months without an alternative medical cause; OR
- •Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy or hysterectomy); OR
- •If subject is of childbearing potential, use of contraception is required while on study treatment and for 6 months after the last dose.
- •Subject must voluntarily sign and date an informed consent, approved by an Institutional Review Board (IRB), prior to the initiation of any research directed screening or procedures.
- •Subject is informed that consumption of the following fruits is prohibited 3 days prior to the initiation of study treatment and throughout participation: grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges) or Star fruit.
排除标准
- •Subject has known active CNS involvement from AML.
- •Subject is known to be positive for HIV. HIV testing is not required.
- •Subject is known to be positive for hepatitis B or C infection with the exception of those with an undetectable viral load. Hepatitis B or C testing is not required and subjects with serologic evidence of prior vaccination to HBV (i.e., HBs Ag, anti-HBs+ and anti-HBc-) may participate.
- •Subject has any history of clinically significant condition(s) that in the opinion of the investigator would adversely affect his/her participating in this study including, but not limited to:
- •Significant active cardiac disease within the previous 6 months including: New York Heart Association heart failure > class 2, unstable angina, or myocardial infarction.
- •Renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, hepatic, cardiovascular disease, or bleeding disorder independent of leukemia.
- •Subject has a malabsorption syndrome or other condition that precludes enteral route of administration. This includes history of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease (e.g. sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
- •Subject exhibits evidence of uncontrolled systemic infection requiring therapy (viral, bacterial or fungal). Uncontrolled is defined as ongoing signs/symptoms related the infection without improvement despite appropriate antibiotics, antiviral therapy and/or other treatment.
- •Subject has a history of other malignancies prior to study entry, with the exception of:
- •Adequately treated in situ carcinoma of the breast or cervix uteri
- •Basal cell carcinoma of the skin or localized squamous cell carcinoma of the skin
- •Prostate cancer not requiring therapy beyond hormonal therapy
- •Previous malignancy confined and surgically resected (or treated with other modalities) with curative intent
- •Subject has a white blood cell count > 25 × 109/L. Note: hydroxyurea or apheresis are permitted to meet this criterion.
- •Any subject who is a candidate for intensive induction therapy and agrees to receive this therapy.
- •Pregnant or breast-feeding females. A pregnancy test will be obtained at the time of screening.
- •Known or suspected hypersensitivity to azacitidine or mannitol.
研究组 & 干预措施
Cohort 1 CC-486 200 mg
CC-486 200 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.
干预措施: Venetoclax (Drug)
Cohort 1 CC-486 200 mg
CC-486 200 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.
干预措施: CC-486 (Drug)
Cohort 2 CC-486 300 mg
CC-486 300 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.
干预措施: Venetoclax (Drug)
Cohort 2 CC-486 300 mg
CC-486 300 mg will be administered orally on days 1-14 of a 28-day cycle. Venetoclax will be administered days 1-3, with the following schema: 100 mg on day 1, 200 mg on day 2, 400 mg on day 3, and it will be continued at 400mg thereafter until day 28, the completion of cycle 1.
干预措施: CC-486 (Drug)
Dose Expansion Cohort
CC-486 MTD will be determine following the completion of Cohort 1 and Cohort 2 with venetoclax at 400 mg/day PI regimen for 28 days.
干预措施: Venetoclax (Drug)
Dose Expansion Cohort
CC-486 MTD will be determine following the completion of Cohort 1 and Cohort 2 with venetoclax at 400 mg/day PI regimen for 28 days.
干预措施: CC-486 (Drug)
结局指标
主要结局
Determine the maximum tolerated dose of CC-486 in combination with venetoclax
时间窗: 7 years
Standard phase I 3+3 design. The first 3 subjects will be assigned to cohort 1. If none of the first three subjects' experiences DLT, escalation to cohort 2 is permitted. If one of the first three subjects' experiences DLT, a total of six subjects will be required in that dose cohort, and escalation will only be permitted if five of six subjects do not experience DLT. If more than one DLT is observed in the second cohort, this will be determined to be the maximally administered dose, and three more subjects will be enrolled in the first cohort if only three were previously treated at that dose. The MTD will be the cohort in which ≤1/6 subjects have dose limiting toxicity at the dose prior to the maximally administered dose. If the second cohort has ≤1/6 subjects with a DLT, the MTD will not have been reached, and the recommended dose for the expansion cohorts will be determined based on the safety, efficacy and pharmacodynamic outcomes from subjects treated in the first two cohorts.
次要结局
- Adverse event profile of CC-486 in combination with venetoclax(7 years)
- Response Rate(5 - 7 years)
- Time to Response(5-7 Years)
- Response Duration(5-7 years)